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Endocrine and Immune System Responses to Stress

INTRODUCTION

The interacting responses of the endocrine and immune systems characterize various forms of stress. Although only partially defined, these responses evolve in combination with stress-induced responses of the central nervous system (CNS).

To encompass the complexities of this neuroendocrine-immune axis, equally complex titles for the field are now emerging, as typified by the term psychoneuroendocrineimmunology. Recent reviews of this subject include a book edited by Chrousos et al. (1988), two conferences of the New York Academy of Sciences (see Bomberger and Haar [1988] and Goetzl et al. [1990]), and a review by Chrousos and Gold (1992).

Molecular participants in these responses to stress include traditional hormones, neuropeptides, immunologically generated cytokines, and the secondary and tertiary messengers formed within responding cells. These

1

William R.Beisel, John Hopkins School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205

The National Academies of Sciences, Engineering, and Medicine 500 Fifth St. N.W. | Washington, D.C. 20001

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10
Endocrine and Immune System Responses to Stress
William R.Beisel1
INTRODUCTION
The interacting responses of the endocrine and immune systems characterize various forms of stress. Although only partially defined, these responses evolve in combination with stress-induced responses of the central nervous system (CNS).
To encompass the complexities of this neuroendocrine-immune axis, equally complex titles for the field are now emerging, as typified by the term psychoneuroendocrineimmunology. Recent reviews of this subject include a book edited by Chrousos et al. (1988), two conferences of the New York Academy of Sciences (see Bomberger and Haar [1988] and Goetzl et al. [1990]), and a review by Chrousos and Gold (1992).
Molecular participants in these responses to stress include traditional hormones, neuropeptides, immunologically generated cytokines, and the secondary and tertiary messengers formed within responding cells. These
1
William R.Beisel, John Hopkins School of Public Health, 615 N. Wolfe Street, Baltimore, MD 21205

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participants in stress responses can act as autocrines, paracrines, or circulating endocrines (or endogenous mediators) with far-ranging effects.
Neuroendocrine-immune system responses to stress are characterized by multiple checks and balances and interacting feedback loops. Other prominent features include redundancy, which is most evident with cytokines, many of which have overlapping activities, plus the ability to enlist related cytokines. Many cytokines also exhibit pleiotropy, with multiple functions (Dantzer and Kelley, 1989).
Neural cells and lymphocytes are capable of producing some of the peptide hormones, and many have receptors that allow them to respond to hormonal stimuli.
Responses of the neuroendocrine-immune axis vary with the form, duration, and severity of the inciting stress. Different patterns of response may also evolve longitudinally, over time, if stress is protracted.
Because the molecular mediators involved in responses to stress show differences in the timing and magnitude of their endogenous production, it is not surprising that their physiologic, metabolic, and nutritional consequences are not consistent. Furthermore, the immunological consequences of stress may impair host defense mechanisms against infectious diseases and malignancies. Host defense mechanisms against infectious diseases are of special concern when military populations are under consideration.
Valuable insights have been obtained by studying responses to stress in laboratory animals. However, because of differences between species, such models may not accurately reflect the stress-induced responses that occur in humans.
HISTORICAL PERSPECTIVES
The first hormone to be discovered, just prior to the turn of the century, was adrenalin (epinephrine), a major contributor to immediate cardiovascular responses to stress. Several decades elapsed, however, before William Cannon, in 1929, summarized his theories of homeostasis and his easily understood concept of “fight or flight” (Kopin et al., 1988).
Contributions of Hans Selye
Two additional decades elapsed before Hans Selye divided stress reactions into three stages: an initial sympathoadrenomedullary “alarm reaction,” a subsequent “stage of resistance” with activation of the hypothalamic-pituitary-adrenocortical axis, and a final stage of exhaustion and death (Kopin et al., 1988).

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Selye’s resistance stage included his general adaptation syndrome. This was characterized by adrenocortical secretion and hypertrophy, gastrointestinal ulceration, and thymic and lymphoid shrinkage. These concepts of Selye gained widespread acceptance, in part because they immediately preceded the clinical availability and use of cortisone and adrenocorticotropic hormone (ACTH).
Selye taught his students that “to measure is to know.” This dictum is reflected in the subsequent logarithmic growth in knowledge during the 1950s, 1960s, and 1970s about each hormone or hormone group. These knowledge bursts depended on advances in steroid and protein chemistry, which allowed hormones and their metabolic products to be assayed in body fluids. Use of radioisotopic iodine was also a major factor in allowing thyroid physiology to be deciphered.
Studies of Endogenous Pyrogen
Following Paul Beeson’s observation (1948) that endotoxin-free substances obtained from neutrophils were capable of inducing fever, many studies of endogenous pyrogen (EP) were initiated. This research consumed much of the professional lifetimes of individuals such as W.Barry Wood, Jr., Elisha Adkins, Phyllis Bodel, and Patrick A.Murphy.
Studies of Infectious Stress
In the early 1960s, Beisel (1991) initiated comprehensive prospective longitudinal studies of the endocrine, metabolic, physiological, and nutritional responses to the stress of infectious disease in research volunteers. These studies were superimposed on ongoing tests of new, experimental vaccines conducted at the U.S. Army Medical Research Institute for Infectious Diseases (USAMRIID).
The USAMRIID group measured day-to-day changes in glucocorticoids and was the first to report increases in aldosterone, growth hormone, insulin, and glucagon during the stress of infectious illnesses and the depression of thyroid function. Similar changes have subsequently been found in individuals with other forms of stress.
However, hormonal changes failed to account for the metabolic and nutritional changes detected in plasma glycoproteins, amino acids, and trace elements or for other components of acute-phase reactions in volunteers (Beisel, 1991). The dilemma was solved, however, by USAMRIID’s discovery of leukocyte products that induced acute-phase reactions and that stimulated endocrine responses as well. These hormone-like substances were originally named leukocytic endogenous mediator(s) (LEMs) (Pekarek and Beisel, 1971);

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they are now called interleukin-1, interleukin-6, and/or tumor necrosis factor, the three “proinflammatory” cytokines.
Studies in Ranger Trainees
Beginning in the late 1970s, a Norwegian group led by Aakvaag and coworkers (1978), Opstad and colleagues (1980, 1981, 1982, 1983, 1984, 1985, 1991, 1992), and Øektedalen (1982, 1983a,b,c) initiated a comprehensive (still ongoing) study of the endocrinological responses of Ranger trainees during 5-day exercises, which included the stresses of food and sleep deprivation as well as severe physical demands. Similar studies have recently been conducted in U.S. Army Rangers. U.S. Army Rangers, who also underwent comprehensive physiological and nutritional measurements as well as immunological studies (Moore et al., 1992)1
Immunological Progress
Logarithmic growth in immunological knowledge also accompanied new research techniques. Identification of populations and subpopulations of T and B lymphocytes in 1968 led to current concepts of the humoral and cell-mediated arms of the immune system and their interrelationships.
Another direction of immunological growth focused on the cytokines. The mutual identity of lymphocyte-activating factor, EP, and LEM was recognized, and in 1979, the three were renamed interleukin-1 (IL-1). The interleukin designation was then used for numerous other cytokines (Beisel, 1991). A few new cytokines may still be identified, but cytokine research still has other major objectives; that is, questions remain about how cytokine genes are regulated, how cytokine gene regulation relates to immune system functions and clinical disease, and how their effects are modulated by circulating cytokine receptors and receptor antagonists.
ENDOCRINE RESPONSES TO STRESS
Most traditional hormones have been implicated in responses to stress, although data on their concentrations in body fluids are relatively scarce and
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Additional data on U.S. Army Ranger trainees were presented at a meeting of the Committee on Military Nutrition Research, Food and Nutrition Board, Institute of Medicine, National Academy of Sciences, in March, 1993 and are referred to here as unpublished data.

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data on production rates are scarcer still. Despite these shortcomings, major hormonal responses to military stresses are now fairly well defined. Hormonal responses to stress are not simply “all out” but are modulated and carefully controlled by feedback loops. Furthermore, CNS peptide mediators that normally function as neurotransmitters may reach concentrations in plasma that allow them to function as hormones (Geelhoed, 1987).
Catecholamines
Acute responses to stress, that is, Cannon’s “fight or flight” and Selye’s “alarm reaction,” focus on catecholamines. These are products of the CNS’s locus ceruleus and the sympathetic nervous system. A dense network of CNS neurons produces norepinephrine, and epinephrine is released from the adrenal medulla and sympathetic nerve terminals (Chrousos and Gold, 1992). These and other neurotransmitters initiate immediate responses to stress (Kopin et al., 1988), including tachycardia, hyperventilation, sweating, piloerection, dilation of pupils and bronchi, vasomotor changes, and altered gut motility.
Increased concentrations of epinephrine and norepinephrine occur during Ranger training (Opstad, 1991; Opstad et al., 1980), as an early component of trauma or surgical stress (Geelhoed, 1887), during intense physical exercise (Landmann et al., 1984), and in patients who suffer strokes (O’Neill et al., 1991) or severe lobar pneumonia (Feldman et al., 1989). Food restriction stress in mice induces gastric ulcers and increases plasma catecholamine values (Nakamura et al., 1990).
Catecholamine responses to infectious disease stress vary with the severity of illness. Although no changes may be detected in subjects with mild, brief infections, increased plasma epinephrine and norepinephrine concentrations urqwoccur in subjects with septic shock (Beisel, 1991) and critically severe infections (Feldman et al., 1989). It should also be noted that vitamin C is required for the production of these catecholamines. The highest concentrations of vitamin C found in the human body are in the catecholamine-producing areas of both the CNS and adrenal glands.
Adrenocortical Responses
Secretion of increased levels of adrenocortical hormones, central to Selye’s general adaptation syndrome, is initiated by corticotropin-releasing factor (CRF) from hypothalamic neurons; this is followed by the release of ACTH from the anterior pituitary gland. Thus, the central hormonal role in stress is

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now often ascribed to CRF (Audhya et al., 1988; Koob et al., 1988; McEwen et al., 1988).
CRF and ACTH
In addition to its role in stimulating greater adrenocorticoid secretion, CRF appears to act in mediating the release of oxytocin, vasopressin, and vasoactive intestinal peptide (Koob et al., 1988; McEwen et al., 1988) and by initiating visceral and paracrine responses to stress (Audhya et al., 1988; Lenz, 1990; Murison and Badde, 1990).
CRF is produced by many CNS neurons in addition to those in the hypothalamus. Its production in the brain’s locus ceruleus gives it a role in stimulating norepinephrine production (Valentino, 1988). Because of its presence in the thymus and spleen, CRF can play a role in neuroimmunomodulation (Audhya et al., 1988; Irwin et al., 1990; Jain et al., 1991). Like CNS opioids, CRF may also have analgesic functions (Bianchi et al., 1991).
Neuronal production of CRF can be stimulated by IL-1 (Rothwell and Grimble, 1992) and platelet-activating factor (PAF) (Rougeot et al., 1990). In contrast, CRF is not stimulated by some stimuli that induce ACTH release, including epinephrine, norepinephrine, angiotensin II, oxytocin, arginine vasopressin, tumor necrosis factor (TNF), IL-2, and IL-6 (Plotsky, 1988; Rothwell and Grimble, 1992). ACTH concentrations in plasma are increased during stress (Chakraborti, 1989; Plotsky, 1988). The responsiveness of adrenocortical cells to ACTH is heightened by immune system activation (Torres-Aleman et al., 1988).
Adrenal Glucocorticoids
The principal glucocorticoids, cortisol in humans and corticosterone in rodents, show relatively modest responses to most stresses. Beisel and coworkers (1967, 1969) found that the normal circadian periodicity of plasma cortisol concentrations was lost during early febrile stages of infections induced in volunteers. Although morning cortisol concentrations were not elevated, the normal circadian decline in cortisol concentrations in the afternoon failed to occur. This combination resulted in a modest increase in 24-h urinary 17-hydroxy-corticosteroids (17-OHCS) excretion (Beisel, 1991).
Increased plasma cortisol concentrations may occur in patients with infections of great severity or terminally ill patients; in such instances, the increased cortisol concentrations can usually be explained by impairment of the hepatic enzymes that convert plasma cortisol to water-soluble metabolites (Beisel, 1991).

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Some of the largest adrenocortical responses occur after trauma or surgical stress (Geelhoed, 1987). However, only modest elevations of plasma cortisol and urinary 17-OHCS have been reported with various other stresses such as heat (Armstrong et al., 1989), high-altitude and cold (Chakraborti, 1989), and in patients with strokes (Mulley et al., 1989; O’Neill et al., 1991).
The stress of Ranger training also is accompanied by a modest adrenocorticoid response (Opstad, 1991, 1992; Opstad and Aakvaag, 1983; Opstad et al., 1980) and a loss of circadian rhythm (Opstad and Aakvaag, 1981). Similar small increases in plasma cortisol concentrations were seen in U.S. Rangers (Moore et al., 1992). Elevations of plasma corticosterone concentrations occur during various forms of experimental stress in rodents (Flores et al., 1990; Kandil and Borysenko, 1988; Kant et al., 1987).
The cortisol response to stress in humans is always proportionally greater than the responses of any other, less potent adrenal glucocorticoids or the adrenal androgens (Beisel, 1991). In fact, adrenal androgen concentrations were found to decrease during Ranger training (Opstad, 1992).
Increased body temperatures caused by the stress of a hot, humid environment produced an adreno-cortical response, along with sizable losses of body nitrogen, electrolytes, and minerals (Beisel et al., 1968).
The physiologic effects (and side effects) of these combined glucocorticoid responses to stress are quite small when compared with those of highly potent synthetic adrenocortical steroids. Furthermore, production of adrenocortical steroids may fall below normal concentrations if disease or surgical stress is protracted (Beisel, 1991; Geelhoed, 1987).
ADRENAL MINERALOCORTICOIDS
The increases in aldosterone concentrations produced during the stress of febrile infections and surgical procedures explains the renal retention of sodium (Beisel, 1991). The increase in aldosterone concentrations may be accompanied by a seemingly inappropriate secretion of antidiuretic hormone, which occurs in some infections, especially those localized within the skull (Beisel, 1991). This combination may lead to retention of dangerous amounts of salt and water.
An increase in the amount of secreted aldosterone and renin has been noted during heat stress (Armstrong et al., 1989) and Ranger training (Opstad et al., 1985).

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Growth Hormone
A stress-induced increase in plasma immunoreactive growth hormone (GH) concentrations was first reported during the stress of infectious disease (Beisel, 1991). Similar increases have been shown to occur in patients with severe pneumonia (Feldman et al., 1989) and have been reported in Norwegian Rangers (Aakvaag et al., 1978; Opstad, 1991; Opstad and Aakvaag, 1981, 1983; Opstad et al., 1980). Six- to 10-fold increases were found in U.S. Army Rangers by MAJ K.Friedl and colleagues (Moore et al., 1992).
Increased GH secretion by the pituitary could be due to growth hormone-releasing factor stimulation (Dieguez et al., 1988) or stress-induced increases in pituitary dopamine values (Aakvaag et al., 1978). It is also possible that lymphocyte secretion of GH could contribute to increased concentrations of GH in plasma (Kelley, 1990).
Thyroidal Responses
Stress-induced activation of the hypothalamic-pituitary-adrenal axis produces secondary suppression of thyroidal responses (Chrousos and Gold, 1992). The concentrations of plasma protein-bound iodine, thyroxine (T4), triiodothyronine (T3), and thyroid-stimulating hormone (TSH) fall during infectious illnesses (Beisel, 1991). The decrease in T3 concentrations can be explained, in part, by an increase in “reverse” T3. These altered values all rebound to normal concentrations during convalescence.
An identical pattern of thyroidal suppression was observed repeatedly during the stress of Ranger training (Opstad and Aakvaag, 1981, 1983; Aakvaag et al., 1978; Opstad et al., 1980, 1984). These Ranger data were compatible with an almost complete halt in thyroidal T4 release (Aakvaag et al., 1978).
Analogous thyroidal suppression occurs in older or poorly conditioned long-distance runners (Hesse et al., 1989). Low thyroid hormone concentrations also characterize traumatic or surgical stress (Geelhoed, 1987).
Other Pituitary Hormones
Like the thyroidal hormone responses, the reproductive hormone axis is inhibited at all levels by components of the hypothalamic-pituitary-adrenal axis (Chrousos and Gold, 1992). Initially, prolactin (PRL) concentrations were thought to be increased by acute stress (Aakvaag et al., 1978), and small increases in PRL concentrations have been found in patients with severe

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pneumonia (Feldman et al., 1989). In contrast, a decline in plasma PRL concentrations was noted in each Ranger group studied (Aakvaag et al., 1978; Opstad and Aakvaag, 1982; Opstad et al., 1980, 1991). These declines in PRL concentrations were minimized by allowing extra sleep time, but not by increasing the daily food intake of the Rangers.
Luteinizing hormone concentrations have shown variable changes in Rangers, with increases and decreases being noted in different groups (Aakvaag et al., 1978; Opstad, 1992; Opstad and Aakvaag, 1983). Another pituitary gonadotropin, follicle-stimulating hormone, showed consistent declines in the plasma of Rangers (Aakvaag et al., 1978; Opstad, 1992).
Testosterone
Testosterone and other androgens share similar fates. Sharp and sustained declines in the concentrations of testosterone and other gonadal androgens occurred in the serum of all Ranger groups tested (Aakvaag et al., 1978; Opstad, 1992; Opstad and Aakvaag, 1983). Declines of 25 and 33 percent were also detected in U.S. Rangers (Moore et al., 1992). It is not known whether testosterone concentration declines were secondary to declines in PRL and the gonadotropin concentrations or whether they were due to some direct testicular effect of heavy exercise.
Pancreatic Hormones
Within 12 h after the onset of fever in infected volunteers, baseline concentrations of both insulin and glucagon in plasma became elevated; glucose tolerance curves and insulin responses also became abnormal, resembling those of adult-onset diabetics (Beisel, 1991). Simultaneous elevations of both insulin and glucagon are most unusual, because these hormones usually act reciprocally. These changes, plus the appearance of cellular insulin resistance, have been attributed to the effects of interleukin-1 (IL-1) (Beisel, 1991).
Increased plasma glucagon values were found in patients with recent strokes (O’Neill et al., 1991). An increase in the insulin concentrations in the plasma of fully fed Rangers was reversed when food restriction stress was added to their training (Opstad and Aakvaag, 1981).

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Intestinal Hormones
Øektedalen et al. (1982, 1983a,b,c) reported three- to sixfold increases in plasma secretin values in fasting Ranger trainees and athletes who participated in long cross-country ski races. These high values rapidly returned to normal after a meal or oral glucose feeding.
Plasma vasoactive intestinal peptive and pancreatic peptide values were also elevated in these ski racers, whose gastric acid secretions showed a threefold increase.
Other Hormones and Neuroendocrines
Nussey et al. (1988) found increases in plasma oxytocin and arginine vasopressin concentrations during surgical stress in elderly patients.
Opioid peptides (endorphins, enkephalins, and dynorphin) are produced by lymphocytes and phagocytic cells as well as by the central nervous system (CNS) (Teschemacher et al., 1990). The stresses of severe exercise, surgery, hyperthermia, and severe pain all trigger the release of beta-endorphin but not methionine-enkephalin (Vescovi etal., 1990). Similar beta-endorphin increases are seen in critically ill children (Dindar et al., 1990).
A depression in the concentrations of insulin-like growth factor (somatomedin C) to 30–50 percent of the baseline concentrations in plasma was measured during all four phases of U.S. Army Ranger training (Moore et al., 1992), despite the concomitant rise in plasma growth hormone values.
IMMUNE SYSTEM RESPONSES TO STRESS
Stress and a variety of psychiatric illnesses, notably the affective disorders, may be associated with immunosuppression (Khansari et al., 1990). However, studies attempting to link various forms of stress to an increased susceptibility to infectious diseases or malignancies seldom include direct measurements of immune system competence.
Sophisticated tests of immune functions have generally not been available in clinical laboratories (although the Acquired Immunodeficiency Syndrome (AIDS) epidemic may be changing that, especially for the important task of counting of helper T-lymphocyte [CD4] numbers). Furthermore, interpretation of delayed dermal hypersensitivity skin tests as a measure of cell-mediated immunity (CMI) requires a competent, well-trained observer.
Nevertheless, the available data suggest that stress may reduce functional immune system competence, especially CMI. Emotional stresses such as the

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death of a family member, divorce, and major depressions all have immunological links, that is, depressed lymphocyte counts and decreased responsiveness of lymphocytes to mitogens (Bonneau et al., 1990).
Changes in Lymphoid Cells and Tissues
Thymic involution, a component of Selye’s general adaptation syndrome, was first recognized in the early 1800s as a component of severe cachexia; it remains a major problem in malnourished children and in adults with disease-induced cachexia. Involution is most prominent in T-cell areas of the thymus and other lymphoid tissues. In contrast, B-cells and plasma cells are usually spared (Beisel, 1991). Stresses that induce cachexia or deficiencies in levels of body zinc can also induce a reversible state of thymic involution. Other stresses can also influence thymic cells; for example, auditory stress in mice inhibits migration of prethymic stem cells into the thymus (Bomberger and Haar, 1988).
Thymic involution is accompanied by reduced production of zinc-containing hormones by thymic epithelial cells. These peptides (thymosin, thymopoietin, thymopentin) have essential roles in the continued maintenance of T-cell functions throughout the body (Beisel, 1991). These thymic peptides can also increase the production of adrenocorticotropic hormone (ACTH) (Khansari et al., 1990) and may play a role in stressful situations.
Lymphocyte Counts in Stress
Reductions in lymphocyte counts, T-cell counts, and CD4/CD8 cell ratios are seen during some stresses (reduced CD4 cell counts in patients with AIDS are attributed to direct viral invasion of those cells). Lymphopenia caused by corticosteroid-induced lympholysis is a phenomenon of rodents but not of humans.
Simultaneous intravenous injections ofcortisol and epinephrine in healthy adult volunteers caused an initial increase in lymphocyte numbers (particularly suppressor CD8 cells and natural killer [NK] cells); these responses were followed by a decline in lymphocyte numbers and then a normalization within 24 h (Brohee et al., 1990).

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CONCLUSIONS
Stress initiates many interacting endocrine, immune system, and central nervous system (CNS) responses. Responses to stress vary widely, depending on the nature, severity, and duration of the stress. Excellent physical conditioning may minimize the magnitude of stress responses.
Endocrine responses to stress have been studied in some detail. Many hormonal changes during stress are components of the acute-phase reaction and tend to be relatively stereotyped.
Acute emotional and physical stresses may evoke immediate CNS-catecholamine responses. Physical and disease-related stresses are generally accompanied by activation of the CNS-pituitary-adrenal axis and increased levels of secretion of aldosterone, growth hormone, and sometimes, insulin and glucagon. In contrast, thyroid hormones, gonadatropins, and androgens show decreased outputs.
More information is needed about stress-induced changes in intestinal hormones and neuroendocrine hormones.
Impairments in both cell-mediated and humoral immunities have been noted during stress, but little is known about the effects of stress on allergic and hypersensitivity reactions. Additional data are needed to define changes in cell-mediated and humoral immunities and lymphocyte subsets (especially natural killer cells and CD4 and CD8 cells) during military stresses.
The major immune system response to stress is the activation of cells that release cytokines, including the triad of interleukins 1 and 6 and tumor necrosis factor, which combine to initiate acute-phase reactions. Military stresses that include strenuous and prolonged physical exercise, numerous cuts and bruises, dermal inflammations, and nagging minor infections are likely to trigger acute-phase reactions, but definitive laboratory data to document the occurrence of such reactions have not yet been obtained. This is an important knowledge gap.
Cytokine-induced acute-phase reactions during stress contribute to deterioration of cognitive and psychomotor performance. Additional studies are needed to determine whether the drugs that block the prostaglandin-releasing actions of the cytokines would prevent or minimize stress-induced (1) decrements of military performance, (2) catabolism of skeletal muscle protein, and (3) catabolic losses of essential micronutrients.
Immune system dysfunctions are caused by protein energy malnutrition and/or inadequacies of certain essential vitamins and minerals. Nutritional rehabilitation with vitamins, minerals, certain amino and fatty acids, and nucleotide precursors appears to hasten immune system recovery.
Similar supplements may have a role in military stresses that generate losses of body weight, muscle mass, and essential micronutrients. There is

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little to suggest, however, that nutritional supplementation of healthy individuals can induce a state of supernormal immunity. Rather, some nutrient excesses can suppress immunological functions.
Studies in animals are needed to evaluate the possible immunological importance of stress proteins in military-type stresses.
RECOMMENDATIONS
First of all, do no harm.
Gather additional data during military stress situations to document the possible occurrence of acute-phase reactions, cell-mediated immune system and humoral immune system dysfunctions, changes in lymphocyte subsets, changes in essential micronutrients, and changes in intestinal hormones and hormonal neurotransmitters.
Conduct studies in animals to explore the possible role of stress proteins in military-type stresses.
If warranted by additional data, protect the immune system during military stress with a daily multivitamin, multimineral preparation. This should include all vitamins in the amounts specified in the Recommended Dietary Allowance (RDAs)plus beta carotene; and the minerals iron, zinc, copper, and selenium, also in RDA amounts.
If new data confirm the occurrence of acute-phase reactions during military stress, the value of drug prophylaxis with ibuprofen (or aspirin) should be tested in an attempt to reduce decrements in performance and the loss of body weight and skeletal muscle mass. The doses of these drugs should be sufficient to minimize the prostaglandin-related effects of acute-phase reactions without masking the symptoms of major infections.
Carefully consider the possible adverse immunological consequences of any nutritional supplement given to enhance military performance.
Remember that the value of nutritional supplements or pharmaceutical agents in preventing performance decrements may equal or exceed their potential value as performance enhancers.
REFERENCES
Aakvaag, A., T.Sand, P.K.Opstad, and F.Fonnum 1978 Hormonal changes in serum in young men during prolonged physical strain. Eur. J. Appl. Physiol. 39:283–291.
Alluisi, E.A., W.R.Beisel, P.J.Bartelloni, and G.D.Coates 1973 Behavioral effects of tularemia and sandfly fever in man. J. Infect. Dis. 128:710–717.